A Temporal Proteomic Map of Epstein-Barr Virus Lytic Replication in B Cells

Ersing, Ina; Nobre, Luis; Wang, Liang Wei; Soday, Lior; Ma, Yijie; Paulo, João A.; Narita, Yohei; Ashbaugh, Camille W.; Jiang, Chang; Grayson, Nicholas; Kieff, Elliott; Gygi, Steven P.; Weekes, Michael P.; Gewurz, Benjamin E.

doi:10.1016/j.celrep.2017.04.062

Cited by 83 publications

(99 citation statements)

References 69 publications

(100 reference statements)

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“…5.1), the complicated regulatory network targeted by EBV latent infection is still being explored. Furthermore, systematic proteomic analyses can possibly validate some of the genomic observations and gain additional insights into EBV-host interactions [67]. In the future, more efficient systems and more advanced technologies with higher resolution, specificity, and sensitivity will be helpful in revealing the complex EBV-host interactions in associated lymphomas.…”

Section: 3 Molecular Biology Of Ebv-mediated B-cell Lymphomasmentioning

confidence: 99%

Current Progress in EBV-Associated B-Cell Lymphomas

Pei

Lewis

2017

Advances in Experimental Medicine and Biology

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Epstein-Barr virus (EBV) was the first human tumor virus discovered more than 50 years ago. EBV-associated lymphomagenesis is still a significant viral-associated disease as it involves a diverse range of pathologies, especially B-cell lymphomas. Recent development of high-throughput next-generation sequencing technologies and in vivo mouse models have significantly promoted our understanding of the fundamental molecular mechanisms which drive these cancers and allowed for the development of therapeutic intervention strategies. This review will highlight the current advances in EBV-associated B-cell lymphomas, focusing on transcriptional regulation, chromosome aberrations, in vivo studies of EBV-mediated lymphomagenesis, as well as the treatment strategies to target viral-associated lymphomas.

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Section: 3 Molecular Biology Of Ebv-mediated B-cell Lymphomasmentioning

confidence: 99%

Current Progress in EBV-Associated B-Cell Lymphomas

Pei

Lewis

2017

Advances in Experimental Medicine and Biology

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“…To avoid the bias inherent in using LCL cells to reactivate memory, we adapted an approach first developed for HSV [3] whereby monocyte-derived dendritic cells cross-present the whole spectrum of virus-coded lytic antigens to the CD8 memory pool. We therefore induced latently-infected 293 cells into lytic cycle and made total cell extracts at a time when >50% cells had already entered late phase and which recent proteomic analysis suggests is optimal for the most complete representation of all lytic antigens [26]. While it is possible that some antigens were absent or under-represented in such extracts, the fact that memory responses were reactivated across the whole spectrum of IE, E and L antigens suggests that antigen representation is not a major problem.…”

Section: Discussionmentioning

confidence: 99%

“…While it is possible that some antigens were absent or under-represented in such extracts, the fact that memory responses were reactivated across the whole spectrum of IE, E and L antigens suggests that antigen representation is not a major problem. Indeed among the targets of these reactivated responses were antigens such as the immune evasin BNLF2a, which is only transiently detectable early in lytic cycle [20], and the portal and scaffold proteins BBRF1 and BdRF1, known to be the least abundant components of the capsid in virus particles [32] and reportedly present at very low concentrations in lytically-infected cells [26]. These considerations and the fact that, for IE and E antigens with already defined target epitopes, the relative strength of antigen-specific memory responses seen in expanded memory cell preparations broadly reflected that seen in ex vivo Elispot assays suggests that such preparations fairly represent the content of virusspecific memory.…”

Section: Discussionmentioning

confidence: 99%

“…However this remains unclear because the precise chronology of antigen expression in early phase is poorly defined. Other factors, such as the rate of de novo antigen synthesis, may be at least as important and it is significant that BALF2, BMRF1, BORF2 and BaRF1 are among the most highly expressed E antigens in lytic cycle [26,32].…”

Section: Discussionmentioning

confidence: 99%

“…From each healthy carrier studied, dendritic cells were prepared by IL4/GMCSF-stimulation of CD14+monocytes as described [3]. These cells were then exposed for 16-20 hrs to a lysate of the HEK-293 epithelial cell line (American Type Culture Collection) carrying the recombinant EBV strain B95.8 genome, made 48 hrs after triggering the latter's induction into lytic cycle, a time judged to be optimal to capture the full gamut of lytic cycle proteins [26]. The antigen-loaded dendritic cell preparation was then co-cultured with autologous lymphocytes and, as described [3], antigen-stimulated memory cells recognised through cell surface up-regulation of the CD137 activation marker.…”

Section: T Cell Responses In Healthy Virus Carriersmentioning

confidence: 99%

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Proteome-Wide Analysis of Cd8+ T Cell Responses to Ebv Reveals Differences Between Primary and Persistent Infection

Forrest

Hislop

Rickinson

et al. 2018

Preprint

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words)Human herpesviruses are antigenically rich agents that induce strong CD8+T cell responses in primary infection yet persist for life, continually challenging T cell memory through recurrent lytic replication and potentially influencing the spectrum of antigen-specific responses. Here we describe the first lytic proteome-wide analysis of CD8+ T cell responses to the Epstein-Barr gamma1-herpesvirus (EBV), and the first such proteome-wide analysis of primary versus memory CD8 responses to any human herpesvirus. Primary effector preparations were generated directly from activated CD8+ T cells in the blood of infectious mononucleosis (IM) patients by in vitro mitogenic expansion. For memory preparations, EBV-specific cells in the blood of long-term virus carriers were first re-stimulated in vitro by autologous dendritic cells loaded with a lysate of lytically-infected cells, then expanded as for IM cells. Preparations from 7 donors of each type were screened against each of 70 EBV lytic cycle proteins in combination with the donor's individual HLA class I alleles. Multiple reactivities against immediate early (IE), early (E) and late (L) lytic cycle proteins, including many hitherto unrecognised targets, were detected in both contexts. Interestingly however, the two donor cohorts showed a different balance between IE, E and L reactivities. Primary responses targeted IE and a small group of E proteins preferentially, seemingly in line with their better presentation on the infected cell surface before later-expressed viral evasins take full hold. By contrast, target choice equilibrates in virus carriage with responses to key IE and E antigens still present but with responses to a select subset of L proteins now often prominent. We infer that, for EBV at least, long-term virus carriage with its low level virus replication and lytic antigen release is associated with a re-shaping of the virus-specific response.3 Author Summary (156 words) Epstein-Barr virus (EBV) is a herpesvirus and an important human pathogen that normally persists for life and induces strong CD8+T cell responses. Primary EBV infection can cause mononucleosis (IM) disease and EBV is associated with malignant lymphocytes cancers and epithelial cells. Here for the first time, we described proteome-wide analysis of CD8+ T cell responses to EBV lytic antigens, and compare the CD8 T cell responses between primary and memory CD8 responses to EBV. The EBV primary CD8 T cells responses targeted IE and a small group of E proteins preferentially. By contrast, the memory CD8 T cells responses from EBV persistent infection are dominated by L proteins. This study can help to understand how human CD8 T cells respond evolves with the long-term virus infection. For EBV at least, we infer that long-term EBV virus carriage with its low level virus replication and lytic antigen release is associated with a re-shaping of the virus-specific response.4

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Epstein−Barr virus reactivation induces MYC‐IGH spatial proximity and t(8;14) in B cells

Sall

Шмакова

Karpukhina

et al. 2023

Journal of Medical Virology

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Burkitt lymphoma (BL) is a B cell malignancy associated with the Epstein−Barr virus (EBV). Most BL cases are characterized by a t(8;14) chromosomal translocation involving the MYC oncogene and the immunoglobulin heavy chain gene (IGH). The role of EBV in promoting this translocation remains largely unknown. Here we provide the experimental evidence that EBV reactivation from latency leads to an increase in the proximity between the MYC and IGH loci, otherwise located far away in the nuclear space both in B-lymphoblastoid cell lines and in patients' B-cells. Specific DNA damage within the MYC locus, followed by the MRE11-dependent DNA repair plays a role in this process. Using a CRISPR/Cas9-based B cell model to induce specific DNA double strand breaks in MYC and IGH loci, we have shown that the MYC-IGH proximity induced by EBV reactivation leads to an increased t(8;14) translocation frequency.

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A Temporal Proteomic Map of Epstein-Barr Virus Lytic Replication in B Cells

Cited by 83 publications

References 69 publications

Current Progress in EBV-Associated B-Cell Lymphomas

Current Progress in EBV-Associated B-Cell Lymphomas

Proteome-Wide Analysis of Cd8+ T Cell Responses to Ebv Reveals Differences Between Primary and Persistent Infection

Epstein−Barr virus reactivation induces MYC‐IGH spatial proximity and t(8;14) in B cells

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